Dr. Preecha Montakantikul
Associate Professor in Clinical Pharmacy,
Department of Pharmacy,
Faculty of Pharmacy, Mahidol University, Thailand

Dr. Taniya Paiboonvong
Pharmacist and Lecturer,
College of Pharmacy,
Rangsit University, Thailand

Sitafloxacin, a broad-spectrum fluoroquinolone with antimicrobial activity against a wide range of pathogenic organisms, is rapidly absorbed after oral administration and has a high bioavailability.¹ Recent evidence suggests a correlation between the pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial agents such as sitafloxacin, which may help in predicting clinical outcomes against microbial pathogens.¹

Dr. Preecha Montakantikul and Dr. Taniya Paiboonyong, based in Thailand, provide a comprehensive overview of the PK/PD of sitafloxacin, and its applications and benefits for use in the treatment of patients with bacterial infection.

Q1: What are the pharmacokinetic features of the sitafloxacin that make it an attractive therapeutic strategy in comparison to other antimicrobial agents?

Dr. Paiboonvong: Sitafloxacin has been approved as an oral formulation in Japan since 2008 and was subsequently approved in Thailand in 2011 for the treatment of urinary tract infection (UTI), including upper and lower respiratory tract infections (RTIs). It is one of the potent respiratory fluoroquinolones, with activity against major pneumonia-causing pathogens (e.g., Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis). The sitafloxacin regimen of 50 or 100 mg twice daily is able to reach the PK/PD target values of clinical dose finding for the treatment of RTIs, whereby the eradication rates are 96.4% (fAUC0–24h/ minimum inhibitory concentration (MIC) ≥30) and 96.3% (fCmax/MIC≥2), respectively.^{1, 2} Most importantly, sitafloxacin showed good activity against multidrug resistant (MDR) pathogens, especially Acinetobacter baumannii which is the major cause of nosocomial infections in Asia. In addition, plasma PK of sitafloxacin exhibited good bioavailability with rapid absorption, and wide distribution into various tissue and body fluid.  Furthermore, sitafloxacin has demonstrated a desirable PK relevant to high penetration into alveolar epithelial lining fluid (ELF), approximately 85–100%, in critically ill patients with pneumonia.³ Therefore, sitafloxacin is a favourable option for the treatment of pneumonia in comparison to beta-lactam antibiotics or colistin.

Q2: In your opinion, could the relative antimicrobial potency of fluoroquinolones including sitafloxacin be explained by differences in pharmacokinetic and pharmacodynamic profiles?

Dr. Montakantikul: Sitafloxacin is a fluoroquinolone antibiotic agent that exhibits concentration-dependent killing activity against various aerobic, anaerobic, Gram-positive and Gram-negative pathogenic bacteria.  According to the population PK study by Tanigawara et al., apparent volume of distribution (Vd/F) of sitafloxacin is 1.72 L/kg.¹ This could explain the wide distribution of sitafloxacin in various body tissues achieving therapeutic level. In addition, sitafloxacin works by inhibiting bacterial DNA gyrase and topoisomerase IV. This inhibitory activity of sitafloxacin has been reported to be greater when compared to other fluoroquinolones.²

Q3: Population PK analysis of sitafloxacin has demonstrated that changes in covariates could influence PK parameters.^{1, 3} What are the implications of these changes to PK with regard to the sitafloxacin treatment strategy and potential clinical outcomes?

Dr. Paiboonvong: Population pharmacokinetics (PPK) modelling is important to help identify and understand demographic covariates that may influence drug disposition and efficacy. In a PK-PD analysis conducted using clinical data of studies of Japanese patients with RTI that received sitafloxacin therapy, renal function (creatinine clearance) was found to be the most significant covariate influencing sitafloxacin concentrations.¹ This could be explained by the cumulative amount of unchanged drug excreted in the urine in approximately 70% of the subjects.¹ In addition, other factors, such as body weight, age, and fasting status, had only slight effects on the C_max and T_max.¹

The PK and penetration of sitafloxacin into alveolar ELF has been studied in critically ill Thai patients with pneumonia.³ The mean±SD (median) maximum ratio of ELF to unbound plasma concentration was 1.02±0.58 (1.33), and penetration ratios based on the mean and median AUC_0–8 were 0.85 and μg.h/ml, respectively. The results indicate that sitafloxacin penetrates well into ELF. However, variability of concentrations observed in these patients comprised of wide ranges in volume of distribution (Vd) and clearance (CL) rates, whereby the mean±SD (median) were 3.13±2.51(2.35) L/kg and 246.13±136.00 (200.86) mL/min, respectively.³ These could be explained by the effect of physiological changes in critically ill patients (e.g. hypoalbuminemia and augmented renal CL), including severity of pneumonia that could have an impact on sitafloxacin penetration. This highlights the important role of PK parameters in causing a change in drug exposure. Based on the available PK/PD data, sitafloxacin has potential benefits for treating severe pneumonia and bacterial infections caused by a drug-resistant pathogens.

Q4a: The emergence of carbapenem-resistant Acinetobacter baumannii (CRAB) poses a significant therapeutic challenge due to a lack of established treatment options.⁴ What is your opinion on the effectiveness of sitafloxacin in combating isolates resistant to fluoroquinolones including CRAB?

Dr. Montakantikul: Carbapenem-resistant Acinetobacter baumannii (CRAB) is one of the major MDR organisms causing high mortality worldwide. The treatment options for infections caused by CRAB remain extremely limited. Currently, colistin or polymyxin B, high-dose sulbactam and high-dose tigecycline are used in the clinical practice.  However, the use of colistin and polymyxin B remains a major concern owing to the potential for renal toxicity. Several new antibiotics such as eravacycline and cefiderocol are not yet available in many countries.⁴

The efficacy of sitafloxacin for CRAB has been demonstrated in at least two in vitro studies in Thailand. Paiboonvong et al. evaluated the in vitro activity of sitafloxacin in 350 A. baumannii clinical isolates collected from thirteen tertiary care hospitals in all regions in Thailand, and found that 278 clinical isolates (79.43%) were MDR-CRAB.⁵  The percentage of susceptibility to sitafloxacin was 64.03% and 90.65%, when the MIC breakpoint was <1 and <2 μg/mL, respectively.⁵ The MIC range, MIC₅₀ and MIC₉₀ of sitafloxacin were ≤0.0625-8 μg/mL, 1 μg/mL and 2 μg/mL, respectively.⁵ Other comparators, including ciprofloxacin, showed susceptibility rate of 8.27%, except colistin, for which the susceptibility rate was 85.25%.⁵ Another in vitro study by Rodjun et al evaluated the synergistic effect between sitafloxacin and colistin in 300 A. baumannii clinical isolates from Thailand, of which 258 (86%) were comprised of CRAB isolates.⁶  The MIC_50/90 of colistin and sitafloxacin in the CRAB isolates were 2/4 mg/L and 1/2 mg/L, respectively.⁶ The percentages of susceptibility of colistin and sitafloxacin in the CRAB isolates were 87.2% and 96.5%, respectively.⁶ The combination of sitafloxacin and colistin resulted in a reduction of MIC₅₀/₉₀ from 2/4 to 0.5/1 mg/L with colistin, and 1/2 to 0.5/1 mg/L with sitafloxacin.⁶ The susceptibility rate also increased to more than 99% for both antibiotic agents.⁶ Therefore, according to the in vitro studies, sitafloxacin showed potential benefit in combating CRAB even in the ciprofloxacin-resistant strains.

Q4b: What is the role of PK-PD properties in determining rational sitafloxacin dosing regimens to manage bacterial infections while reducing the risk of antibiotic resistance?

Dr. Montakantikul: Strategies to optimise antimicrobial dosing regimens have been receiving more attention owing to the alarming rise of MDR pathogens such as CRAB. Applications of PK/PD analysis in combination with Monte Carlo simulation allows optimisation of dosing regimens of antibiotic agents in order to conserve their therapeutic value. In this regard, Monte Carlo simulation is an advanced statistical modelling tool that helps to predict of the likely results of different therapeutic approaches and achievement of targets. Numerous Monte Carlo simulation studies of antibiotic agents have shown benefit in determining antibiotic dosage regimens, including sitafloxacin combinations. One of our ongoing studies (unpublished data) shows that the appropriate dosage of sitafloxacin against CRAB is higher than the recommended dose. Therefore, the PK-PD properties of sitafloxacin could help to determine the optimal dosing regimen, fostering more rational and individualised dosing regimens to reduce underuse or overuse of agents.

References

1. Tanigawara Y, et al. J Infect Chemother 2013;19(5):858–66.
2. Keating GM, et al. Drugs 2011;171(6):731–44.
3. Paiboonvong T, et al. Antimicrob Agents Chemother 2019; 63(10): e00800–19.
4. Bartal C, et al. Infect Dis Ther 2022; 11(2): 683–694.
5. Paiboonvong T, et al. Pharm Sci Asia 2020;47(1):37–
6. Rodjun V, et al. Antibiotics 2020;9:516.